Therapies targeted to inhibit the activity of the EGF pathway through its receptor (EGFR) have seen increased application in anti-cancer therapy (Sawyers C., Nature 432: 294-297, 2004). The EGF pathway can be inhibited by injections of monoclonal antibodies (antibody inhibitors) targeting an extracellular epitope of the EGFR, or by chemical agents (small molecule inhibitors) that inhibit the receptor tyrosine kinase on the cytoplasmic side of cancer cells (Sawyers, 2004; Imai and Takaoka, Nat Rev Cancer. 2006 September; 6(9):714-27).
Erlotinib (Tarceva®) is approved as a first-line and maintenance treatment, and 2nd or 3rd-line treatment for advanced-stage non-small cell lung cancer. It is an orally administered reversible EGFR tyrosine kinase inhibitor (TKI) targeting the EGF receptor, which is up-regulated in the majority of lung, colorectal, and head and neck cancers (Schettino et al., 2008 April; 2(2):167-78).
These anti-cancer therapies, such as Erlotinib, have demonstrated success and are a welcomed addition to the fight against cancer. However, there are also significant drawbacks associated with the utilization of the aforementioned EGFR receptor antagonists. These drawbacks, which will be elaborated upon below, decrease patient compliance with the therapeutic and also limit the patient populations that can be effectively treated by the EGFR antagonistic compounds.
For example, EGFR activation is required for active epithelial Mg-absorption/reabsorption that is mediated by the transient receptor potential cation channel, subfamily M, member 6 (TRPM6) channel in the kidney and colon (Tejpar et al., Lancet Oncol. 2007, 8: 387-394). Treatment of patients with monoclonal antibodies (cetuximab and panitumumab) targeting the EGFR in colorectal cancer were found to cause pronounced hypomagnesemia (Tejpar et al., 2007; Petrelli et al., Expert Opinion on Drug Safety, May 2012, Vol. 11, No. 51, Pages S9-S19). Noticeable hypomagnesemia was also observed in patient receiving cetuximab plus erlotinib (Janjigian et al., Clin Cancer Res. 2011 Apr. 15; 17(8):2521-7). The association of hypomagnesemia with EGFR antagonistic compounds is troublesome and represents a serious drawback for utilizing these compounds as anti-malignant agents.
Further, Erlotinib can provoke cellular oxidative stress in cancer cells through NOX-4 up-regulation (Fletcher et al., Mol Cancer Res., 2013 December; 11(12):1574-84, Epub 2013 Sep. 18; Orcutt et al., Cancer Res. 2011 Jun. 1; 71(11):3932-40, Epub 2011 Apr. 11). Previous work has shown that an experimental TKI, tyrphostin AG 1478, which is chemically similar to erlotinib, displayed substantial cardiac dysfunctional effects, that were associated with enhanced neurogenic inflammation (elevated circulating levels of substance P (SP)), oxidative stress, and hypomagnesemia (Weglicki et al., Can. J. Physiol. Pharmacol. 2012; 90(8):1145-9).
The present disclosure shows that chronic treatment of rats with an EGFR blocking drug, such as erlotinib, induces significant: hypomagnesemia, systemic oxidative stress, cardiac dysfunction, and skin lesions and rashes. Thus, the present disclosure not only supports some of the previous findings regarding negative effects associated with utilization of EGFR blocking therapeutics, but it also elucidates further insights into the potentially harmful side effects associated with such.
Consequently, there is a great need in the medical community for the development of novel therapeutic compounds, compositions, and methods of treatment, which help to alleviate the aforementioned deleterious side effects associated with administration of EGFR blocking agents in human patients.